(1) Field of the Invention
The present invention generally relates to diagnosis and therapy of type 1 diabetes. More specifically, the invention provides compositions and methods for diagnosis, prevention and therapy of type 1 diabetes based on the identification of islet β cell antigens targeted by pathogenic T cells.
(2) Description of the Related Art
References Cited
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In both humans and NOD mice, type 1 diabetes (T1D) is an autoimmune disease that results from T cell-mediated destruction of insulin-producing pancreatic β cells and involves complex interactions among developmental, genetic, and environmental factors (Serreze and Leiter, 2001a; 2001b; Roep, 2003). In the NOD mouse model, spontaneous autoimmune diabetes development requires both CD4+ and CD8+ T cells (Christianson et al., 1993; Serreze et al., 1994; Wicker et al., 1994; Wang et al., 1996; DiLorenzo et al., 1998), with evidence suggesting that CD8+ T cells are required for the initial stages of β cell destruction (Wang et al., 1996; DiLorenzo et al., 1998). Although there are multiple susceptibility loci, the strong association of particular MHC class II molecules with disease has led to extensive investigation of CD4+ T cells in T1D (Lieberman and DiLorenzo, 2003). However, several studies in NOD mice have documented the importance of pathogenic CD8+ T cells in the initial stages of β cell destruction (DiLorenzo et al., 1998, Serreze et al., 1994; Wong et al., 1996; Wicker et al., 1994).
Several NOD-derived, β cell-autoreactive CD8+ T cell clones have been reported (DiLorenzo et al., 1998; 2002; Gurlo et al., 1999; Nagata et al., 1994; Wong et al., 1996; Shimizu et al., 1993); however, only three of these (designated G9C8, 8.3, and AI4) have demonstrated in vivo pathogenicity.
The 8.3 clone represents a prevalent population of islet-specific glucose-6-phosphatase catalytic subunit-related protein206-214 (IGRP206-214)-reactive T cells present in NOD islets throughout disease development and progression to overt diabetes (DiLorenzo et al., 1998; Santamaria et al., 1995; Lieberman et al., 2003; Amrani et al., 2000; Trudeau et al., 2003). The pathogenicity of 8.3 is demonstrated by the accelerated rate of diabetes development observed in 8.3 TCR transgenic NOD mice that is enhanced by CD4+ T cell help (Verdaguer et al., 1997), and by adoptive transfer studies (Nagata et al., 1994; Utsugi et al., 1996).
The insulin B15-23-reactive pathogenic CD8+ T cell clone G9C8 has been shown to cause diabetes in the absence of CD4+ T cell help, but these experiments involved transfer of previously activated G9C8 T cells into recipient mice; thus, their ability to develop and mature in the absence of CD4+ T cell help is unknown (Wong et al., 1996; 1999).
Both the 8.3 clone and the G9C8 clone are H-2Kd-restricted (Wong et al., 1999; Lieberman et al., 2003).
The AI4 CD8+ T cell clone, originally isolated from the islets of a 5-week-old female NOD mouse (DiLorenzo et al., 1998), represents one of these β cell-autoreactive specificities. NOD mice transgenically expressing the AI4 TCR (designated NOD.AI4αβ Tg) progress to overt diabetes significantly earlier than nontransgenic NOD mice (Graser et al., 2000). Strikingly, this accelerated diabetes development is also observed in NOD-scid.AI4αβ Tg, NOD.CD4null.AI4αβ Tg (Graser et al., 2000), and NOD.Rag1null.AI4αβ Tg mice (DiLorenzo et al., 2002), all of which lack CD4+ T cells. Hence, naïve AI4 T cells are able to develop, mature, and mediate sufficient β cell destruction to cause accelerated disease in the complete absence of CD4+ T cell help. AI4 represents the only diabetogenic CD8+ T cell clone known to be capable of doing so.
We recently showed that AI4 recognizes a β cell peptide (still unidentified) that is distinct from these two (DiLorenzo et al., 2002). Thus, AI4 represents a third antigenic specificity contributing to early β cell destruction in NOD mice. However, to date, only mimotope ligands for AI4 have been identified (Serreze et al., 2004).
There is thus a need to characterize the AI4 clone, by identifying mimotopes capable of activating AI4-like T cells and allowing β cell destruction, and by identifying the β cell antigen having that binding specificity.